The mitochondrial aldehyde dehydrogenase (ALDH2) is the major ALDH isozyme involved in acetaldehyde metabolism. It is well established that a single nucleotide substitution (G to A) which results in the amino acid change (Glu487Lys) leads to dominant inactivation of ALDH2 activity. This genetic polymorphism is the cause of the flushing response observed in many Asian people following alcohol intake. Although the ALDH2-2 allele has been shown to have a protective role against alcoholism, the physiological role of this enzyme is still unclear. To further examine the possible physiological role of ALDH2, we produced transgenic mice carrying the human ALDH2 variant (Haldh2-2). Currently, we have established two independent lines of Haldh2 transgenic mice. These mice were used to study the effects of Haldh2 on alcohol preference, metabolism of endogenous and exogenous substrates, behavior and tissue damage after long-term alcohol consumption. Human ALDH2 protein was expressed in all tissues examined and expression of human ALDH2-2 inhibited mouse ALDH2 enzyme activity in transgenic mice. Mice were injected with 20% ethanol ip for over two weeks. We observed that fubin background strain mice showed fear, avoidance and escape behavior after ethanol-treatment but these changes in behavior were not evident in the transgenic mice exposed to ethanol (p<0.001). To correlate the apparent behavioral change with levels of neurotransmitters and to study the role of ALDH2 in endobiotic metabolism, the levels of various monoamine neurotransmitters were determined by HPLC. In brain, dopamine and its metabolite, 3.4-dihydroxyphenyl acetic acid (DOPAC), were significantly elevated in FVB/N mice treated with ethanol. In contrast, this elevation was absent in transgenic mice. Brain serotonin level was also elevated by ethanol treatment but to a lesser extent than dopamine level. Brain norepinephrine was unchanged in any of the strains. These results suggest that behavioral differences in the transgenics are due to alteration in monoamine metabolism by the introduction of Haldh2-2. Our preliminary data also indicate that female transgenic mice consume 40% less alcohol (p<0.0001) than do FVB/N background mice in a two-bottle choice paradigm. No significant difference was observed in male transgenic mice. These data indicate that transgenic mice carrying the Haldh2-2 can be a valuable model to study the role of ALDH in behavior, neurotransmitter metabolism and drinking preference.